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Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

RationaleObstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.ObjectivesTo define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts.MethodsGenome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration.Measurements and main resultsTwo novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P

ObjectiveObstructive sleep apnea (OSA) is very common in Parkinson's disease (PD). OSA is known to affect patients' cognition. The present study assessed whether PD patients with OSA (PD + OSA) score lower on cognitive measures than those without OSA (PD - OSA). In addition, this study evaluated whether treating the OSA with continuous positive airway pressure (CPAP) in PD + OSA patients results in an improved cognitive functioning.MethodsEighty-six patients with PD underwent an overnight polysomnography screen for OSA and were administered the Mini-Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). This resulted in 38 patients with PD + OSA who were randomly assigned to receive either therapeutic CPAP for 6 weeks (n = 19) or placebo CPAP for three weeks followed by therapeutic CPAP for three weeks (n = 19). Intervention participants completed a neurocognitive battery at baseline and 3- and 6-week time-points.ResultsPatients with PD + OSA scored significantly lower than PD - OSA on the MMSE and MoCA after controlling for age, education, and PD severity. OSA was a significant predictor of cognition (MMSE p

RationaleWhen obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) coexist in the so-called "overlap" syndrome, a high risk for mortality and morbidity has been reported. There is controversy about the prevalence of OSA in people affected by COPD.ObjectivesThe purpose of this study was to investigate objective meaures of sleep-disordered breathing in patients with moderate to severe COPD to test the hypothesis that COPD is associated with an increased prevalence of OSA.MethodsFifty-four patients (54% men) with moderate to severe COPD were enrolled prospectively (mean ± SD, FEV1 = 42.8 ± 19.8% predicted, and FEV1/FVC = 42.3 ± 13.1). Twenty patients (37%) were on supplemental oxygen at baseline. Exercise tolerance; questionnaires related to symptoms, sleep, and quality of life; and home polysomnography were obtained.Measurements and main resultsForty-four patients had full polysomnography suitable for analysis. OSA (apnea-hypopnea index > 5/h) was present in 29 subjects (65.9%). Sleep efficiency was poor in 45% of subjects.ConclusionsOSA is highly prevalent in patients with moderate to severe COPD referred to pulmonary rehabilitation. Sleep quality is also poor among this selected group. These patients have greater-than-expected sleep-disordered breathing, which could be an important contributory factor to morbidity and mortality. Pulmonary rehabilitation programs should consider including a sleep assessment in patients with moderate to severe COPD and interventions when indicated to help reduce the impact of OSA in COPD.

ObjectiveWe evaluated the association between obstructive sleep apnea (OSA) and neurocognitive function among community-dwelling Hispanic/Latino individuals in the United States.MethodsCross-sectional analysis of the Hispanic Community Health Study/Study of Latinos middle-aged and older adults, aged 45 to 74 years, with neurocognitive test scores at baseline measurements from 2008 to 2011. Neurocognitive scores were measured using the Word Fluency (WF) Test, the Brief-Spanish English Verbal Learning Test (SEVLT), and the Digit Symbol Substitution (DSS) Test. OSA was defined by the apnea-hypopnea index (AHI). Multivariable linear regression models were fit to evaluate relations between OSA and neurocognitive scores.ResultsThe analysis consisted of 8,059 participants, mean age of 56 years, 55% women, and 41% with less than high school education. The mean AHI was 9.0 (range 0-142; normal AHI

ObjectiveRapid eye movement (REM)-sleep behavior disorder (RBD) is often comorbid with Parkinson's disease (PD). The current study aimed to provide a detailed understanding of the impact of having RBD on multiple non-motor symptoms (NMS) in patients with PD.MethodsA total of 86 participants were evaluated for RBD and assessed for multiple NMS of PD. Principal component analysis was utilized to model multiple measures of NMS in PD, and a multivariate analysis of variance was used to assess the relationship between RBD and the multiple NMS measures. Seven NMS measures were assessed: cognition, quality of life, fatigue, sleepiness, overall sleep, mood, and overall NMS of PD.ResultsAmong the PD patients, 36 were classified as having RBD (objective polysomnography and subjective findings), 26 as not having RBD (neither objective nor subjective findings), and 24 as probably having RBD (either subjective or objective findings). RBD was a significant predictor of increased NMS in PD while controlling for dopaminergic therapy and age (p=0.01). The RBD group reported more NMS of depression (p=0.012), fatigue (p=0.036), overall sleep (p=0.018), and overall NMS (p=0.002).ConclusionIn PD, RBD is associated with more NMS, particularly increased depressive symptoms, sleep disturbances, and fatigue. More research is needed to assess whether PD patients with RBD represent a subtype of PD with different disease progression and phenomenological presentation.

Study objectivesObstructive sleep apnea (OSA), common in Parkinson disease (PD), contributes to sleep disturbances and daytime sleepiness. We assessed the effect of continuous positive airway pressure (CPAP) on OSA, sleep, and daytime sleepiness in patients with PD.DesignThis was a randomized placebo-controlled, crossover design. Patients with PD and OSA were randomized into 6 w of therapeutic treatment or 3 w of placebo followed by 3 w of therapeutic treatment. Patients were evaluated by polysomnography (PSG) and multiple sleep latency test (MSLT) pretreatment (baseline), after 3 w, and after 6 w of CPAP treatment. Analyses included mixed models, paired analysis, and within-group analyses comparing 3 w to 6 w of treatment.SettingSleep laboratory.ParticipantsThirty-eight patients with PD (mean age = 67.2 ± 9.2 y; 12 females).InterventionContinuous positive airway pressure.MeasurementsPSG OUTCOME MEASURES: sleep efficiency, %sleep stages (N1, N2, N3, R), arousal index, apnea-hypopnea index (AHI), and % time oxygen saturation < 90% (%time SaO2 < 90%). MSLT outcome measures: mean sleep-onset latency (MSL).ResultsThere were significant group-by-time interactions for AHI (P < 0.001), % time SaO2 < 90% (P = 0.02), %N2 (P = 0.015) and %N3 (P = 0.014). Subjects receiving therapeutic CPAP showed significant decrease in AHI, %time SaO2 < 90%, %N2, and significant increase in %N3 indicating effectiveness of CPAP in the treatment of OSA, improvement in nighttime oxygenation, and in deepening sleep. The paired sample analyses revealed that 3 w of therapeutic treatment resulted in significant decreases in arousal index (t = 3.4, P = 0.002). All improvements after 3 w were maintained at 6 w. Finally, 3 w of therapeutic CPAP also resulted in overall decreases in daytime sleepiness (P = 0.011).ConclusionsTherapeutic continuous positive airway pressure versus placebo was effective in reducing apnea events, improving oxygen saturation, and deepening sleep in patients with Parkinson disease and obstructive sleep apnea. Additionally, arousal index was reduced and effects were maintained at 6 weeks. Finally, 3 weeks of continuous positive airway pressure treatment resulted in reduced daytime sleepiness measured by multiple sleep latency test. These results emphasize the importance of identifying and treating obstructive sleep apnea in patients with Parkinson disease.

Study objectivesTo evaluate the impact of sleep disorders on non-motor symptoms in patients with Parkinson disease (PD).DesignThis was a cross-sectional study. Patients with PD were evaluated for obstructive sleep apnea (OSA), restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and REM sleep behavior disorder (RBD). Cognition was assessed with the Montreal Cognitive Assessment and patients completed self-reported questionnaires assessing non-motor symptoms including depressive symptoms, fatigue, sleep complaints, daytime sleepiness, and quality of life.SettingSleep laboratory.Participants86 patients with PD (mean age = 67.4 ± 8.8 years; range: 47-89; 29 women).InterventionsN/A.Measurements and resultsHaving sleep disorders was a predictor of overall non-motor symptoms in PD (R(2) = 0.33, p < 0.001) while controlling for age, PD severity, and dopaminergic therapy. These analyses revealed that RBD (p = 0.006) and RLS (p = 0.014) were significant predictors of increased non-motor symptoms, but OSA was not. More specifically, having a sleep disorder significantly predicted sleep complaints (ΔR(2) = 0.13, p = 0.006), depressive symptoms (ΔR(2) = 0.01, p = 0.03), fatigue (ΔR(2) = 0.12, p = 0.007), poor quality of life (ΔR(2) = 0.13, p = 0.002), and cognitive decline (ΔR(2) = 0.09, p = 0.036). Additionally, increasing number of sleep disorders (0, 1, or ≥ 2 sleep disorders) was a significant contributor to non-motor symptom impairment (R(2) = 0.28, p < 0.001).ConclusionIn this study of PD patients, presence of comorbid sleep disorders predicted more non-motor symptoms including increased sleep complaints, more depressive symptoms, lower quality of life, poorer cognition, and more fatigue. RBD and RLS were factors of overall increased non-motor symptoms, but OSA was not.

ObjectivesTo assess the usefulness of actigraphy for assessment of nighttime sleep measures in patients with Parkinson's disease (PD).DesignParticipants underwent overnight sleep assessment simultaneously by polysomnography (PSG) and actigraphy.SettingOvernight sleep study in academic sleep research laboratory.ParticipantsSixty-one patients (mean age 67.74 ± 8.88 y) with mild to moderate PD.MeasurementsSleep measures including total sleep time (TST), sleep efficiency (SE), wake after sleep onset (WASO), and sleep onset latency (SOL) were calculated independently from data derived from PSG and from actigraphy. Different actigraphy scoring settings were compared.ResultsNo single tested actigraphy scoring setting was optimal for all sleep measures. A customized setting of an activity threshold of 10, with five consecutive immobile minutes for sleep onset, yielded the combination of mean TST, SE, and WASO values that best approximated mean values determined by PSG with differences of 6.05 ± 85.67 min for TST, 1.1 ± 0.641% for SE, and 4.35 ± 59.56 min for WASO. There were significant but moderate correlations between actigraphy and PSG measurements (rs = 0.496, P < 0.001 for TST, rs = 0.384, P = 0.002 for SE, and rs = 0.400, P = 0.001 for WASO) using these settings. Greater disease stage was associated with greater differences between TST (R(2) = 0.099, beta = 0.315, P = 0.018), SE (R(2) = 0.107, beta = 0.327, P = 0.014), and WASO (R(2) = 0.094, beta = 0.307, P = 0.021) values derived by actigraphy and PSG explaining some of the variability. Using a setting of 10 immobile min for sleep onset yielded a mean SOL that was within 1 min of that estimated by PSG. However SOL values determined by actigraphy and PSG were not significantly correlated at any tested setting.ConclusionsOur results suggest that actigraphy may be useful for measurement of mean TST, SE, and WASO values in groups of patients with mild to moderate Parkinson's disease. However, there is a significant degree of variability in accuracy among individual patients. The importance of determining optimal scoring parameters for each population studied is underscored.

IntroductionObstructive sleep apnea (OSA) is common among patients with Alzheimer's disease (AD). Untreated OSA exacerbates the cognitive and functional deficits. Continuous positive airway pressure (CPAP) has recently been shown to have beneficial effects on cognition in AD. Little attention has focused on the long-term benefits of CPAP in these patients.MethodsThis was an exploratory study of sustained CPAP use (mean use = 13.3 months, SD = 5.2) among a subset of participants from an initial 6-week randomized clinical trial (RCT) of CPAP in patients with mild to moderate AD. Follow-up included 5 patients who continued CPAP (CPAP+) after completion of the RCT and 5 patients who discontinued CPAP (CPAP-), matched by time of completion of the initial study. A neuropsychological test battery and sleep/mood questionnaires were administered and effect sizes were calculated.ResultsEven with a small sample size, sustained CPAP use resulted in moderate-to-large effect sizes. Compared to the CPAP- group, the CPAP+ group showed less cognitive decline with sustained CPAP use, stabilization of depressive symptoms and daytime somnolence, and significant improvement in subjective sleep quality. Caregivers of the CPAP+ group also reported that their own sleep was better when compared to the final RCT visit and that their patients psychopathological behavior was improved.ConclusionThe results of this preliminary study raise the possibility that sustained, long-term CPAP treatment for patients with AD and OSA may result in lasting improvements in sleep and mood as well as a slowing of cognitive deterioration. Prospective randomized controlled research trials evaluating these hypotheses are needed.